The BCL-2 family comprises an essential network of proteins that govern the cell's decision to live or die. BIM, a pro-apoptotic BH3-only protein of the BCL-2 family is a master regulator of B-cell homeostasis and its functional suppression is believed to be a key pathogenic factor in B-cell lymphoma. The goal of this proposal is to investigate and modulate this critical, deregulated component of the apoptotic pathway in B-cells and apply the mechanistic insights to advance a novel therapeutic strategy for reactivating cell death in treatment- refractory lymphoma. I hypothesize that the potency of BIM BH3 in triggering cell death reflects its capacity to engage a diversity of key protein targets and death pathways, and that pharmacologic replacement of BIM's "death domain" using a hydrocarbon-stapled peptide will restore cell death for therapeutic benefit in B-cell lymphoma. I will apply a multidisciplinary approach to (1) test the capacity of a hydrocarbon-stapled BIM BH3 helix to reactivate the death program in B-cell lymphomas driven by distinct mechanisms of apoptotic blockade, (2) identify the explicit protein targets of BIM SAHB to link cellular activity to in situ mechanism of action, (3) determine the therapeutic potential of pharmacologic BIM BH3 replacement in mouse models of human and murine B-cell lymphoma. By intertwining chemistry, lymphoma biology, and developmental therapeutics, I aim to generate fresh mechanistic insight into the pro-apoptotic potency of the BH3-only protein BIM and determine how this unique BH3 death domain can be harnessed to reactivate cell death in diverse B-cell lymphomas driven by distinct and clinically-relevant chemoresistance mechanisms. A 5-year comprehensive training program led by a diverse team of internationally-recognized mentors, collaborators, and advisors with expertise in the fields of synthetic chemistry, immunology, apoptosis biology, and clinical hematology/oncology will provide an ideal training environment for Dr. LaBelle's development into an independent investigator with unique expertise at the interface of chemical biology and cancer medicine. PUBLIC HEALTH RELEVANCE: Relapsed and treatment-refractory B-cell lymphoma arises from the cancer cell's ability to establish a variety of formidable roadblocks that prevent natural cell death. By intertwining chemistry, lymphoma biology, and preclinical studies, I aim to define the susceptibility patterns and protein targets of BIM, a potent death- activating protein of the BCL-2 family network, responsible for triggering lymphoma cell death and advance a novel strategy to restore the BIM functionality using a stapled peptide. We believe the proposed studies, which employ novel research tools and prototype therapeutics, will provide fresh insight into the biology and treatment of chemoresistant B-cell lymphoma. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.